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1.
Front Physiol ; 12: 690531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34385933

RESUMO

Excessive mucus production is a major feature of allergic asthma. Disruption of epithelial junctions by allergens such as house dust mite (HDM) results in the activation of ß-catenin signaling, which has been reported to stimulate goblet cell differentiation. ß-catenin interacts with various co-activators including CREB binding protein (CBP) and p300, thereby regulating the expression of genes involved in cell proliferation and differentiation, respectively. We specifically investigated the role of the ß-catenin/CBP signaling pathway in goblet cell metaplasia in a HDM-induced allergic airway disease model in mice using ICG-001, a small molecule inhibitor that blocks the binding of CBP to ß-catenin. Female 6- 8-week-old BALB/c mice were sensitized to HDM/saline on days 0, 1, and 2, followed by intranasal challenge with HDM/saline with or without subcutaneous ICG-001/vehicle treatment from days 14 to 17, and samples harvested 24 h after the last challenge/treatment. Differential inflammatory cells in bronchoalveolar lavage (BAL) fluid were enumerated. Alcian blue (AB)/Periodic acid-Schiff (PAS) staining was used to identify goblet cells/mucus production, and airway hyperresponsiveness (AHR) was assessed using invasive plethysmography. Exposure to HDM induced airway inflammation, goblet cell metaplasia and increased AHR, with increased airway resistance in response to the non-specific spasmogen methacholine. Inhibition of the ß-catenin/CBP pathway using treatment with ICG-001 significantly attenuated the HDM-induced goblet cell metaplasia and infiltration of macrophages, but had no effect on eosinophils, neutrophils, lymphocytes or AHR. Increased ß-catenin/CBP signaling may promote HDM-induced goblet cell metaplasia in mice.

2.
Allergy ; 75(8): 1902-1917, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32460363

RESUMO

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single-cell RNA sequencing (scRNA-Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.


Assuntos
Asma , Alérgenos , Asma/genética , Células Epiteliais , Epitélio , Humanos , Mucosa Respiratória , Sistema Respiratório
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